Signal transducer and activator of transcription 2 (STAT2), the critical component of type I interferons signaling, is a prototype latent cytoplasmic signal-dependent transcription factor. Activated tyrosine-phosphorylated STAT2 associates with STAT1 and IRF9 to bind the ISRE elements in the promoters of a subset of IFN-inducible genes (ISGs). In addition to activate hundreds of ISGs, IFN␣ also represses numerous target genes but the mechanistic basis for this dual effect and transcriptional repression is largely unknown. We investigated by ChIP-chip the binding dynamics of STAT2 and "active" phospho(P)-STAT2 on 113 putative IFN␣ direct target promoters before and after IFN␣ induction in Huh7 cells and primary human hepatocytes (PHH). STAT2 is already bound to 62% of our target promoters, including most "classical" ISGs, before IFN␣ treatment. 31% of STAT2 basally bound promoters also show P-STAT2 positivity. By correlating in vivo promoter occupancy with gene expression and changes in histone methylation marks we found that: 1) STAT2 plays a role in regulating ISGs expression, independently from its phosphorylation; 2) P-STAT2 is involved in ISGs repression; 3) "activated" ISGs are marked by H3K4me1 and H3K4me3 before IFN␣; 4) "repressed" genes are marked by H3K27me3 and histone methylation plays a dominant role in driving IFN␣-mediated ISGs repression.Interferons are pleiotropic cytokines induced upon virus infection and other stimuli to modulate host immune response and are classified as type I interferon ␣ and  (IFN␣ and IFN), 3 type II (IFN␥), and the recently discovered type III (IFN) (1-3)). Interferons exert their function by phosphorylating latent transcription factors belonging to the signal transducer and activator of transcription (STAT) family after a signaling cascade, which begins with the binding of interferon to their membrane receptors and involves Janus kinases (JAKs). Receptor dimerization or oligomerization leads to Jak apposition and the trans-phosphorylation on tyrosine residues that releases their intrinsic catalytic activity. Tyrosine-phosphorylated cytokine-receptor cytoplasmic domains then provides binding sites for the Src homology-2 (SH2) domain of the STAT proteins, which are recruited to the JAKs and phosphorylated on a single tyrosine residue (Tyr-689 in the case of STAT2). The interaction between phosphorylated-SH2 domains on STAT proteins leads to homo-or hetero-dimerization and nuclear translocation (4 -6). STAT2 Tyr-689 and STAT1 Tyr-701 can also be phosphorylated by non-receptor TKs, including SRC and ABL in the absence of ligand-induced receptor signaling (7). STAT dimers directly activate genes containing the IFN␥ activation site (GAS) element, while the association of STATs with the DNA-binding protein interferon regulatory factor (IRF) 9 expands the range of DNA response elements that can be targeted by the JAK-STAT pathway to interferon-stimulate response element (ISRE) and IRF response element (IRE) (8). Un-phosphorylated STAT2 binds IRF9 and constitutively shuttles i...
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